A Novel Mutation in MSX1 is Associated with Selective Posterior Tooth Agenesis

Tooth agenesis is a clinically heterogeneous disorder affecting specific tooth types at different rates. Recent evidence also confirms the role of genetic heterogeneity in this common dental anomaly, with two genes, MSX1 and PAX9; contributing to the majority of cases published. Previous studies have associated mutations in PAX9 with molar oligodontia, while others have associated mutations in MSX1 primarily with premolar hypodontia. We recently excluded the involvement of PAX9 in two families with a pattern of molar oligodontia similar to the first described family. Objective: Our objective was therefore to determine if mutations in MSX1 might also be responsible for a pattern of tooth agenesis predominantly involving molar teeth. Methods: To test whether mutations in MSX1 are responsible for familial posterior tooth agenesis, we analyzed a family with this phenotype where PAX9 was previously excluded. Clinical examination, pedigree analysis, followed by PCR-based mutational analysis of MSX1 was carried out for affected individuals, unaffected relatives and unrelated controls. Utilizing a sensitive SNP detection method termed pyrosequencing, 4 affected individuals, 5 unaffected relatives and unrelated controls were screened for the presence of a rearrangement in exon 1 of MSX1. Results: Pedigree analysis revealed that posterior tooth agenesis was transmitted as an isolated autosomal dominant trait in this family. Direct sequencing of the coding region of MSX1 revealed a complex rearrangement involving a GAG insertion and C deletion at nucleotide 250. Our SNP detection assay also confirmed the presence of a mutation in all affected family members but not in unaffected individuals. Conclusion: Our results support the conclusion that posterior tooth agenesis is due to genetic heterogeneity, and suggests that MSX1 may cooperate with PAX9 in the patterning of human dentition. Supported by the AAOF (SF-B), UT-HSC (SF-B), THECB-ATP 00494901431999 (RDS), and NIH grant R01 DE13668 (RDS and SF-B), and UCRC M01RR02558.